Exploring the neurobiology of the premonitory phase of migraine preclinically - a role for hypothalamic kappa opioid receptors?
Exploring the neurobiology of the premonitory phase of migraine preclinically - a role for hypothalamic kappa opioid receptors?
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临床上探索偏头痛的前阶段的神经生物学 - 下丘脑Kappa阿片受体的作用？
DOI：
10.1186/s10194-022-01497-7
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发表时间：
2022-09-30
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偏头痛的先兆期部分表现为口渴、排尿和打哈欠。影像研究表明，下丘脑在先兆阶段被激活。应激是一种众所周知的偏头痛启动因素，它被证明在包括下丘脑在内的几个大脑区域参与强啡肽/kappa阿片受体(KOR)信号的传递。这项研究建议在啮齿动物模型中探索下丘脑KOR和偏头痛先兆症状之间的可能联系。用KOR激动剂U-69,593对大鼠进行系统治疗，然后进行打哈欠和排尿监测。阿朴吗啡是一种多巴胺D1/2激动剂，作为打哈欠行为的阳性对照。对全身应用U-69,593后的排尿和用水量也进行了评估。将AAV8-hSyn-DIO-hM4Di(GI-DREADD)-mCherry病毒载体显微注射到雌性和雄性KORCRE或KORWT小鼠的右侧弓状核(ARC)内，观察KOR在下丘脑的特异性激活是否能促进先兆症状。注射4周后，全身注射氯氮平(CNO)，然后评估排尿、用水量和触觉反应。全身注射U-69,593可增加大鼠的排尿次数，但不会引起打哈欠。全身KOR激动剂也增加了小鼠的尿量和水的消耗。ARC内KORCRE神经元的细胞特异性GI-DREADD激活(即通过GI偶联信号抑制)也增加了小鼠的用水量和总尿量，但不影响触觉感觉反应。我们在啮齿动物身上的研究发现，下丘脑区域的KOR是一种促进与临床观察到的偏头痛先兆症状一致的行为的机制，包括口渴和排尿增加，但不打哈欠。重要的是，这些行为发生在没有疼痛反应的情况下，与头痛阶段之前的先兆期的出现一致。甚至在头痛阶段之前就进行预防性治疗的早期干预，可以通过靶向下丘脑KOR来实现。网上版载有补充材料，可在10.1186/s10194-022-01497-7查阅。
The migraine premonitory phase is characterized in part by increased thirst, urination and yawning. Imaging studies show that the hypothalamus is activated in the premonitory phase. Stress is a well know migraine initiation factor which was demonstrated to engage dynorphin/kappa opioid receptors (KOR) signaling in several brain regions, including the hypothalamus. This study proposes the exploration of the possible link between hypothalamic KOR and migraine premonitory symptoms in rodent models. Rats were treated systemically with the KOR agonist U-69,593 followed by yawning and urination monitoring. Apomorphine, a dopamine D1/2 agonist, was used as a positive control for yawning behaviors. Urination and water consumption following systemic administration of U-69,593 was also assessed. To examine if KOR activation specifically in the hypothalamus can promote premonitory symptoms, AAV8-hSyn-DIO-hM4Di (Gi-DREADD)-mCherry viral vector was microinjected into the right arcuate nucleus (ARC) of female and male KORCRE or KORWT mice. Four weeks after the injection, clozapine N-oxide (CNO) was administered systemically followed by the assessment of urination, water consumption and tactile sensory response. Systemic administration of U-69,593 increased urination but did not produce yawning in rats. Systemic KOR agonist also increased urination in mice as well as water consumption. Cell specific Gi-DREADD activation (i.e., inhibition through Gi-coupled signaling) of KORCRE neurons in the ARC also increased water consumption and the total volume of urine in mice but did not affect tactile sensory responses. Our studies in rodents identified the KOR in a hypothalamic region as a mechanism that promotes behaviors consistent with clinically-observed premonitory symptoms of migraine, including increased thirst and urination but not yawning. Importantly, these behaviors occurred in the absence of pain responses, consistent with the emergence of the premonitory phase before the headache phase. Early intervention for preventive treatment even before the headache phase may be achievable by targeting the hypothalamic KOR. The online version contains supplementary material available at 10.1186/s10194-022-01497-7.
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影响因子：
2.9
作者：
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通讯作者：
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